Alzheimer's disease (AD), the onset of which occurs mainly in the later years of life, is a neurodegenerative disease causing progressive dementia.
In AD, neuropathologic examination of the brain reveals in most patients the presence of neuritic plaques, abnormal neurites, and neurofibrillary tangles containing paired helical filaments composed of cross-linked polypeptides that are especially prominent in the cerebral cortex and hippocampal formation. The mechanism of progression of the disease is unknown. The phenotype heterogeneity of the disease makes diagnosis difficult and definite diagnoses can be made only after detection of characteristic pathological changes such as neurofibrilla tangles and neuritic plaques..sup.1 Different etiologies have been attributed to AD, one of which has a possible immunological basis..sup.15
The role of the immune system in the pathogenesis of Alzheimer's disease has been widely researched,.sup.20,25,27 but the exact role of the immune system has not been clearly established. The fact that immune functions change with age is also well documented..sup.16,30,34,40 Published reports indicate a number of discrepancies concerning immunological indices associated with AD,.sup.27 including several studies on cytokine secretion by mononuclear cells of AD patients as compared to age-matched controls,.sup.4,29,36 and cytokine serum levels in patients with AD..sup.8,10 These studies suggest that immune interactions exist between the central nervous system and peripheral blood lymphocytes of AD patients. Since AD is no longer viewed today as a single unified clinical condition, but as a complex syndrome,.sup.14 it has been postulated that the presence of different clinical subgroups may imply a differential involvement of the immune system..sup.23,24,35
U.S. Pat. No. 4,728,605 to Fudenberg et al. further teaches the association of the immune system in the pathogenesis of AD, the teachings of which are incorporated herein by reference.
The presence of cytokines and their receptors in the brain, as well as the endogenous synthesis of cytokines, such as IL-1, IL-3 and IL-6, has been documented..sup.7,9,18,32 The physiological functions of these cytokines are virtually unknown. However, in light of the view that there is an active and highly-regulated communication between the brain and the immune system,.sup.6,28 and as cytokines are known to function via a cascade effect, applicants postulate a link between the cytokine profile in the blood stream and that in the brain which, in turn, may have a bearing on the appearance of neurological diseases and subsequent disease progression.
There are many forms of dementia presenting with symptoms similar to AD. Many of these other conditions are treatable, such as brain tumors, thyroid and other endocrine dysfunctions, depression, infection, vitamin and mineral deficiencies, metabolic disorders, unrecognized injuries and medication side effects. AD is not treatable and so diagnosis is critical. In general, AD is diagnosed using behavioral symptoms and psychological scoring which involve subjective judgements. U.S. Pat. Nos. 4,728,605, 4,886,743, 5,015,570, 5,017,470, 5,100,645, and 5,231,001 present objective methods of diagnosing AD.
However, none of the above methods determine the stage or progression of the disease, i.e., the severity of the disease. Specifically, none of the above-listed patents or studies show any correlation between impaired cytokine production in AD and the disease stage of the patient. The determination of disease progression is still dependent on the behavioral symptoms and psychological scoring which involve subjective judgements.
Currently, the only existing FDA-approved drug for Alzheimer's is tacrine hydrochloride (Cognex.TM., Warner-Lambert) which is very expensive, has extensive side effects, and has been shown to be effective only in the mild stages of the disease. Therefore, an objective method of diagnosing AD at the early stages would be useful in eliciting maximal effect from this drug.